title: The effects of intrathecal and systemic gabapentin on spinal substance P release.
abstract: BACKGROUND
  Gabapentin binds at the extracellular α2δ1 subunit of voltage- sensitive calcium channels. Some voltage-sensitive calcium channels regulate substance P release from small primary afferents. We sought to determine in vivo whether spinal and systemic gabapentin at antihyperalgesic doses will attenuate substance P release.
  
  
  METHODS
  Rats prepared with chronic intrathecal (IT) catheters received IT vehicle or gabapentin 10 minutes before intraplantar formalin (5%, 50 μL) injection. For systemic studies, vehicle or gabapentin was delivered intraperitoneally (IP) 15 minutes before formalin injection. In separate groups of rats, to assess the effect of IT or IP gabapentin upon formalin-evoked substance P release, animals received similar treatment for assessment of flinching, but underwent transcardial perfusion with 4% paraformaldehyde 10 minutes after the formalin injection. Substance P release was determined by the incidence of neurokinin 1 receptor (NK1r) internalization in the ipsilateral and contralateral superficial dorsal horn in immunofluorescent stained tissues.
  
  
  RESULTS
  Unilateral intraplantar formalin evoked biphasic hindpaw flinching. IT gabapentin (100 and 200 μg) and IP gabapentin (100 and 200 mg/kg) resulted in a dose-dependent reduction in phase 2, but not phase 1, flinching in comparison with vehicle-treated rats. Intraplanatar formalin resulted in NK1r internalization in the ipsilateral, but not contralateral, superficial dorsal horn. IT gabapentin (200 μg, but not 100 μg) and IP gabapentin (200 mg/kg, but not 100 mg/kg) significantly reduced ipsilateral NK1r internalization in comparison with vehicle-treated control. Importantly, internalization evoked by IT substance P was not blocked by IT gabapentin.
  
  
  CONCLUSIONS
  Systemic and spinal gabapentin have an acute inhibitory effect on the release of substance P from small primary afferents and a concurrent effect upon the initiation of facilitated pain states.
authors.affiliation: Department of Anesthesiology, Dokkyo Medical University, School of Medicine, Tochigi, Japan.
authors.forename: Toshifumi
authors.initials: T
authors.lastname: Takasusuki
authors.forename: Tony L
authors.initials: TL
authors.lastname: Yaksh
mesh_terms: D000588:Amines / Q000008:administration & dosage*; D000818:Animals; D003509:Cyclohexanecarboxylic Acids / Q000008:administration & dosage*; D000077206:Gabapentin; D007274:Injections, Intraperitoneal; D007278:Injections, Spinal; D008297:Male; D010147:Pain Measurement / Q000187:drug effects* / Q000379:methods; D051381:Rats; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000187:drug effects* / Q000378:metabolism*; D013373:Substance P / Q000378:metabolism*; D005680:gamma-Aminobutyric Acid / Q000008:administration & dosage*
chemical_list: D000588:Amines; D003509:Cyclohexanecarboxylic Acids; D013373:Substance P; D005680:gamma-Aminobutyric Acid; D000077206:Gabapentin